PROJECT SUMMARY This application addresses a set of targeted health issues through a Cooperative Research Agreement with the World Trade Center (WTC) Health Program (UO1). WTC rescue and recovery workers have experienced multiple illnesses as documented in longitudinal studies. WTC dust is a complex mixture of asbestos, silica, benzene, polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons, volatile organic compounds and metals (Zeig-Owens, 2011, Li et al., 2012, Solan et al., 2013). The presence of such carcinogens and inflammation inducers in WTC dust has raised the concern that those exposed to the WTC environment after its collapse could have an increased cancer risk. To date, there have been three cohort studies indicating that total cancer rates are 6-14% above background rates with statistically significant increased rates for thyroid and prostate cancer (Zeig-Owens, 2011, Li et al., 2012, Solan et al., 2013). While precise exposure measurements were not performed, estimates of increased exposure based on workers' time of arrival and proximity to the WTC as well as duration of exposure were associated with increased risk of tumor progression (de la Hoz, Christie et al. 2008). Despite these correlative data, the contribution of WTC dust exposure to tumorigenesis has not been evaluated in a cause and effect manner. Our preliminary observations indicate that WTC dust exposure alters the functions of immune cells. Our evidence indicates that the inflammatory responses elicited by WTC dust can affect tumor cell migration and induce an epithelial to mesenchymal (EMT) gene signature in ways that could contribute to more aggressive prostate tumors observed in WTC rescue and recovery workers observed in our preliminary data. Moreover, inflammation is known to be associated both with prostate cancer progression and carcinogen exposure. This project is designed to test these hypotheses and to evaluate the consequences of acute and chronic WTC dust exposure using genetically engineered mouse (GEM) models of prostate cancer. These prospective data will be correlated with studies of prostate tumor tissues from cancer patients among WTC responders. The goals are to elucidate possible mechanisms by which WTC dust may induce diseases in those at risk, how the inflammatory responses induced by WTC dust may correlate with biomarkers identified in human prostate tumor tissues, and whether prostate tumor progression in mouse models may be ameliorated through control of the inflammatory response and application of cancer immune modulatory therapies.